The present invention relates to novel indole and 2,3-dihydroindole derivatives which are potent serotonin reuptake inhibitors, pharmaceutical compositions containing these compounds and the use thereof for the treatment of disorders or diseases responsive to the inhibition of serotonin re-uptake. The compounds of the invention also possess antagonistic activity at 5-HT1A receptors and are considered to be particularly useful for the treatment of depression.
Selective serotonin (or 5-HT) reuptake inhibitors (SSRI""s) such as fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram represent a major step forward in the treatment of depression because they have fewer and less severe side effects compared to first generation antidepressant (tricyclics and non-selective MAO inhibitors). The side effects associated with first generation antidepressants are such that they cause some patients to withdraw from treatment.
SSRI""s and all other antidepressants currently available suffer from a serious drawback in that several weeks of treatment is necessary to produce the therapeutic effect. The late onset of action is a significant problem, particularly in the treatment of patients with severe depression and suicide potential. Further, one in three patients are not responsive to SSRI""s.
Electrophysiological experiments in rats have shown that acute administration of SSRIs reduces firing of 5-HT neurons of dorsal raphe nucleus in the rodent brain, whereas sustained treatment with SSRIs leads to normalization of the firing activity of the 5-HT neurons (Arborelius, L. et al, Naunyn-Schmiedeberg""s Arch. Pharmacol1995, 352, 157; Gartside, S. E. et al, Br. J. Pharmacol. 1995, 115, 1064; Chaput, Y. et al, Naunyn-Schmiedeberg""s Arch. Pharmacol. 1986, 33, 342).
Further, it has been shown that the recovery of the firing activity of 5-HT neurons is linked to desensitization of somatodendritic 5-HT1A autoreceptors (Le Poul, E. et al, Naunyn-Schmiedeberg""s Arch. Pharmacol. 1995, 352, 141; Invernizzi, R. et al, Eur. J. Pharmacol. 1994, 260, 243).
It has thus been suggested that simultaneous administration of SSRIs and an agent causing rapid desensitization or inhibition of the 5-HT1A receptor mediated feed back mechanism would lead to rapid onset of antidepressive effect (Artigas, F. et al, Trends Neurosci. 1996, 19, 378; De Vry, J., et al, Drug News Perspec. 1996, 9, 270).
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT1A receptor antagonist has been evaluated in several studies (Innis, R. B. et al., Eur. J. Pharmacol., 1987, 143, p 195-204 and Gartside, S. E., Br. J. Pharmacol. 1995, 115, p 1064-1070, Blier, P. et al, Trends Pharmacol. Sci. 1994, 15, 220). In these studies it was found that 5-HT1A receptor antagonists inhibit the decrease in firing caused by acute administration of serotonin reuptake inhibitors.
Further, treatment with a combination of pindolol (a well known 5-HT1A receptor and xcex2-adrenoceptor antagonist) and SSRI""s has been evaluated in clinical trials. A remarkable improvement of the mood of patients was reported within one week. In addition, combined administration of pindolol and a SSRI was shown to have a good effect on patients who were non-responsive to treatment with currently available antidepressants (Artigas F. et al., Arch. Gen. Psychiatry, 1994, 51, p 248-251 and Blier, P. et al., J. Clin. Psychopharmacol. 1995, 15, p 217-222).
Several patent applications have been filed which cover the use of a combination of a 5-HT1A antagonist and a serotonin reuptake inhibitor for the treatment of depression (see EP-A2-687 472 and EP-A2-714 663).
In EP-A1-529 462 certain 1,4-benzodioxan derivatives having the general formula 
wherein B is an optionally substituted indol-3-yl group and Q is CnH2n wherein n is 1, 2, 3, 4, 5, or 6 are disclosed. These compounds are said to have serotonin agonistic and serotonin antagonistic activity as well as serotonin reuptake inhibiting activity and to be useful as anxiolytics, antidepressants, antipsychotics, antihypertensives, and cerebroprotective agents.
In U.S. Pat. No. 5,200,948, Perregaard et al., disclose related indoles, indazoles, 2-indolones and 2,3-dihydro derivatives thereof having the formula 
wherein X is xe2x80x94CHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94COxe2x80x94; and Ar is 
wherein Y is O, or S, Z is O, S, or xe2x80x94CH2xe2x80x94, and n is 1, 2, or 3.
These compounds are valuable 5-HT1A receptor ligands.
It is the object of the present invention to provide compounds with potent serotonin reuptake inhibiting activity as well as antagonistic properties at 5-HT1A receptors. Such compounds may be useful as fast onset of action medicaments for the treatment of affective disorders, such as depression.
A further object of the present invention is to provide a pharmaceutical composition comprising the above compounds as active ingredients.
The invention then, inter alia, comprises the following alone or in combination:
An indole or 2,3-dihydro-indole derivative having the formula 
any of its enantiomers or any mixture thereof, or an acid addition salt thereof, wherein
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CR4R5xe2x80x94; and
Y is xe2x80x94CR6R7xe2x80x94, xe2x80x94CR6R7xe2x80x94CR8R9xe2x80x94, or xe2x80x94CR6xe2x95x90CR7xe2x80x94; or
X and Y together form a group xe2x80x94CR4xe2x95x90CR5xe2x80x94, or xe2x80x94CR4xe2x95x90CR5xe2x80x94CR6R7xe2x80x94;
Z is xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94;
W is N, C, or CH;
A is a group selected from a group of formula (II), (III) and (IV) 
xe2x80x83wherein the dotted lines mean an optional bond;
R1, R2, R3, R12, R13, R14, R15, R16 and R17 are each independently selected from halogen, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, hydroxy, formyl, acyl, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, nitro, cyano, and aryl or arylalkyl wherein aryl may be substituted with halogen, trifluoromethyl, alkoxy, hydroxy,amino, alkylamino, nitro and cyano;
R4, R5, R6, R7, R8 and R9 are each independently selected from hydrogen and alkyl; and
R11 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, acyl and formyl.
In one embodiment of the invention Z is xe2x80x94Oxe2x80x94, and the other substituents are as defined above.
In another embodiment of the invention Z is xe2x80x94Sxe2x80x94 and the other substituents are as defined above.
In a third embodiment of the invention A is a group of formula (II) and the other substituents are as defined above.
In a fourth embodiment of the invention A is a group of formula (III) and the other substituents are as defined above.
In a fifth embodiment of the invention A is a group of formula (IV) and the other substituents are as defined above.
Thus, in a special embodiment of the invention A is a group of formula (II) and Z is xe2x80x94O, A is a group of formula (III) and Z is xe2x80x94Oxe2x80x94, A is a group of formula (IV) and Z is xe2x80x94Oxe2x80x94, A is a group of formula (II) and Z is xe2x80x94Sxe2x80x94, A is a group of formula (III) and Z is xe2x80x94Sxe2x80x94 or A is a group of formula (IV) and Z is xe2x80x94Sxe2x80x94.
In a further embodiment of the invention R4, R5, R6, R7, R8 and R9 are selected from hydrogen or methyl.
Examples of compounds according to the invention are
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2-methyl-1H-indole,
6-Chloro-3-[2-[4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-chloro-1H-indole,
6-Chloro-3-[2-[4-(2,2, -dimethyl-2,3-dihydrobenzofuran-7-yl) piperidin-1-yl]ethyl]-
6-Chloro-3-[2-[4-(2,2, -dimethyl-2,3, -dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methoxy-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methyl-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-methyl-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,
6-Chloro-3-[2-[4-(5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)piperizin-1yl]ethyl]-1H-indole,
6-Chloro-3-[2-[4-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl)piperazin-1-yl]ethyl]-1H-indole,
6-Chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-methyl-1H-indole,
3-[2-[4-(7-Chloro-1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
2-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-2,3-dihydroindole,
6-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(1,4-Benzodioxin-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(Benzofuran-7-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, and
3-[2-[4-(1,3-Benzodioxolan4-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
6-Chloro-3-[2-[4-(6-Chloro-1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indol,
5-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,
3-[2-[4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(Benzothiophen-7-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole,
3-{2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl}-6-chloro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole,
6-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-1H-indole,
3-[2-[4-(Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-bromo-1H-indole,
3-[2-[4-(Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-5-bromo-1H-indole,
1-Acetyl-3-[2-[4-(1,4-benzodioxan-4-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole,
1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,
1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole,
1-[2-[4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-5-fluoro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-2,3-dihydro-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-butyl-1H-indole,
1-Allyl-3-[2-[4-(1,4-benzodioxan-5 -yl)piperazin-1-yl]ethyl]-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5 -propargyl-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1-methyl-1H-indole,
3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-l -benzyl-2,3-dihydro-1H-indole,
1-Allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole,
1-Acetyl-3-[2-[4 -(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole,
3-[2-[4-(Benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(Benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(Benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(Benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(Benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, and
3-[2-[4-(Benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,
or an acid addition salt thereof.
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent
In a further embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the inhibition of serotonin reuptake and antagonism of 5-HT1A receptors.
In particular, the invention relates to the use of a compound according to the invention or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive compulsive disorder.
In still another embodiment, the present invention relates to a method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the inhibition of serotonin reuptake and antagonism of 5-HT1A receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
In particular, the invention relates to a method for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive compulsive disorder comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof to a living animal body, including a human, in need thereof.
Due to their combined antagonism of 5-HT1A receptors and serotonin reuptake inhibiting effect, the compounds of the invention are considered particularly useful as fast onset of action medicaments for the treatment of depression. The compounds may also be useful for the treatment of depression in patients who are resistant to treatment with currently available antidepressants.
The compounds claimed herein are considered particularly useful for the treatment of depression requiring fast onset of antidepressive effect, or a depression which is resistant to other antidepressants.
Halogen means fluoro, chloro, bromo, or iodo.
Alkyl means a straight or branched chain of one to four carbon atoms, including for example; methyl, ethyl, propyl, isopropyl and butyl.
Alkenyl means a chain of from two to four carbon atoms containing one double bond, including for example ethenyl, 1-,2-propenyl, 2-,3-propenyl etc.
Alkynyl means a chain of from two to four carbon atoms containing one triple bond, including for example ethynyl, 1-,2-propynyl, 2-,3-propynyl etc.
Cycloalkyl means cyclic alkyl of from three to seven carbon atoms, including cyclopropyl, cyclobutyl etc.
Alkoxy is xe2x80x94O-alkyl where alkyl is as defined above.
Acyl means xe2x80x94CO-alkyl wherein alkyl is as defined above.
Alkylamino means xe2x80x94NH-alkyl, and dialkylamino means xe2x80x94Nxe2x80x94(alkyl)2 where alkyl is as defined above.
Acylamino means xe2x80x94NH-acyl wherein acyl is as defined above.
Alkoxycarbonylamino means alkyl-Oxe2x80x94COxe2x80x94NHxe2x80x94 wherein alkyl is as defined above.
Alkylaminocarbonylamino means alkyl-NHxe2x80x94COxe2x80x94NHxe2x80x94 wherein alkyl is as defined above.
Dialkylaminocarbonylamino means (alkyl)2xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94 wherein alkyl is as defined above.
Aryl means an aromatic ring such as phenyl, or napthyl.
Arylalkyl means aryl-alkyl wherein aryl and alkyl is as defined above.
Exemplary of organic acid addition salts according to the invention are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.
Further, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (i.e. enantiomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallization of d- or I- (tartrates, mandelates, or camphorsulphonate) salts for example. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
The compounds of the invention can be prepared by one of the following methods comprising:
a) reducing the carbonyl groups of a compound of formula 
xe2x80x83wherein R1-R3, R12, R14-R17, X, Y, Z, W, and the dotted line are as defined above;
b) alkylating an amine of formula 
xe2x80x83wherein R1-R3, X, Y, Z, W, and the dotted line are as defined above with a reagent of formula Gxe2x80x94CH2CH2xe2x80x94A wherein A is as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
c) reductive alkylation of an amine of formula 
xe2x80x83wherein R1-R3, X, Y, Z, W, and the dotted line are as defined above with a reagent of formula Bxe2x80x94CH2xe2x80x94A, wherein A is as defined above and B is either an aldehyde or a carboxylic acid group;
d) reducing the double bond of indoles of formula 
xe2x80x83wherein R1-R3, X, Y, Z, W and the dotted line are as defined above and Axe2x80x2 is a group of formula (II), (III), or (IV) as above in which the dotted line represents a bond, in order to obtain the corresponding 2,3-dihydroindole derivatives;
e) reducing the double bond of the tetrahydropyridines of formula 
xe2x80x83wherein R1-R3, A, X, Y, and Z are as previously defined, in order to obtain the corresponding piperidine derivatives;
f) treating a compound of general formula (I) wherein Y is xe2x80x94CR6xe2x95x90CR7xe2x80x94, or wherein X and Y together form a group xe2x80x94CR4xe2x95x90CR5xe2x80x94, or xe2x80x94CR4xe2x95x90CR5xe2x80x94CR6R7 with a reducing agent in order to reduce the double bond, thereby obtaining a corresponding reduced ring system;
g) reductive removal of one or more of the substituents R1-R3 or R12-R17 in a compound of general formula (I) in which one or more of these substituents are selected from chloro, bromo, or iodo;
h) dialkylating an amine of formula 
xe2x80x83wherein R1-R3, X, Y and Z is as defined above with a reagent of formula 
xe2x80x83wherein A is as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
i) dialkylating an amine of formula 
xe2x80x83wherein A is as defined above with a reagent of formula 
xe2x80x83wherein R1-R3, X, Y, Z and W is as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate; or
j) alkylating or acylating the indole nitrogen atom of compounds of formula 
xe2x80x83wherein R1-R3, X, Y, Z, W, and the dotted line are as defined above , and Axe2x80x3 is a group selected from a group of formula (III), or (IV) as above in which R11 is hydrogen with alkylating or acylating reagents of formula R11xe2x80x94G, wherein G is suitable a leaving group such as halogen, mesylate, or tosylate and R11 is as defined above but not hydrogen;
whereupon the compounds of formula (I) are isolated as the free base or in the form of an acid addition salt thereof.
The reduction according to method a) is preferably carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran in the presence of lithium aluminium hydride at reflux temperature. Starting compounds of formula (V) are generally prepared from reagents of formula (VI), 1,3-unsubstituted indoles, and oxalyl chloride as described in the examples which follow.
The alkylation according to method b) is conveniently performed in an inert organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of a base (potassium carbonate or triethylamine) at reflux temperature.
Arylpiperazine derivatives of formula (VI) are conveniently prepared from the corresponding arylamine according to the method described by Martin et al, J. Med. Chem., 1989, 32, 1052, or the method described by Kruse et al, Rec. Trav. Chim. Pays-Bas, 1988, 107, 303. The starting arylamines are either commercially available or are well-described in the literature.
Aryltetrahydropyridine derivatives of formula (VI) are known from literature, cf. U.S. Pat. No. 2,891,066; McElvain et al, J. Amer. Chem. Soc. 1959, 72, 3134. Conveniently, the corresponding arylbromide is lithiated with BuLi followed by addition of 1-benzyl4-piperidone. Subsequent treatment with acid gives the N-benzyl-aryltetrahydropyridine. The benzyl group can be removed by catalytic hydrogenation or by treatment with e.g. ethyl chloroformate to give the corresponding ethyl carbamate followed by acidic or alkaline hydrolysis. The starting arylbromides are either commercially available or well-described in the literature.
Reagents of formula Gxe2x80x94CH2CH2xe2x80x94A are either commercially available or can be prepared by literature methods, e.g. from the corresponding acetic acid derivative by reduction to the 2-hydroxyethyl derivative and conversion of the hydroxy group to the group G by conventional methods.
The reductive alkylation according to method c) is performed by standard literature methods. The reaction can be performed in two steps, i.e. coupling of (VI) and the reagent of formula Bxe2x80x94CH2xe2x80x94A by standard methods via the carboxylic acid chloride or by use of coupling reagents such as e.g. dicyclohexylcarbodiimide followed by reduction of the resulting amide with lithium aluminium hydride. The reaction can also be performed by a standard one-pot procedure. Carboxylic acids or aldehydes of formula Bxe2x80x94CH2xe2x80x94A are either commercially available or described in the literature.
Reduction of the indole double bond according to method d) is conveniently performed by treatment with diborane or a diborane precursor such as the trimethylamine or dimethylsulfide complex in an inert solvent such as e.g. tetrahydrofuran or dioxane from 0xc2x0 C. to reflux temperature followed by acid catalyzed hydrolysis of the intermediate borane derivative. The reduction can alternatively be performed by treatment with sodium cyanoborohydride in trifluoroacetic acid.
Reduction of the double bonds according to methods e) and f) is most conveniently perfomed by hydrogenation in an alcohol in the presence of a noble metal catalyst, such as e.g. platinum or palladium.
The removal of halogen substituents according to method g) is conveniently performed by catalytic hydrogenation in an alcohol in the presence of a palladium catalyst or by treatment with ammonium formate in an alcohol at elevated temperatures in the presence of a palladium catalyst.
The dialkylation of amines according to methods h) and i) is most conveniently performed at elevated temperatures in an inert solvent such as e.g. chlorobenzene, toluene, N-methylpyrrolidone, dimethylformamide, or acetonitrile. The reaction might be performed in the presence of base such as e.g. potassium carbonate or triethylamine. Starting materials for processes h) and i) are commercially available or can be prepared from commercially available materials using conventional methods.
The N-alkylation according to method j) is performed in an inert solvent such as e.g. an alcohol or ketone at elevated temperatures in the presence of base, e.g. potassium carbonate or triethylamine at reflux temperature. Alternatively, a phase-transfer reagent can be used.